Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease

Department of Internal Medicine, Sections on Cardiology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 06/2002; 22(6):1012-7. DOI: 10.1161/01.ATV.0000018301.91721.94
Source: PubMed

ABSTRACT Oral contraceptive use in women with factor V Leiden is associated with increased rates of venous thromboembolic events (VTEs). However, the effects of hormone replacement therapy (HRT) in postmenopausal women with factor V Leiden are not known. A nested case-control study was conducted among women with established coronary disease enrolled in 2 randomized clinical trials of HRT, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Estrogen Replacement and Atherosclerosis (ERA) trial. The Leiden mutation was present in 8 (16.7%) of 48 cases with VTE compared with only 7 (6.3%) of 112 controls (odds ratio [OR](Leiden) 3.3, 95% CI 1.1 to 9.8; P=0.03). In women without the factor V Leiden mutation, risk associated with HRT use was significantly increased (OR(HRT) 3.7, 95% CI 1.4 to 9.4; P<0.01). On the other hand, in women with the factor V Leiden mutation, the estimated risk associated with HRT was increased nearly 6-fold, although the CIs were wide and included unity (OR(HRT) 5.7, 95% CI 0.6 to 53.9; P=0.13). The OR for women with the Leiden mutation who were also assigned to HRT compared with wild-type women assigned to placebo was 14.1 (95% CI 2.7 to 72.4, P=0.0015). In women with the factor V Leiden mutation who were treated with HRT, the estimated absolute incidence of VTE was 15.4 of 1000 per year compared with 2.0 of 1000 per year in women without the mutation who were taking a placebo (P=0.0015). On the basis of these data, in women with coronary disease, the estimated number needed to screen for factor V Leiden to avoid an HRT-associated VTE during 5 years of treatment is 376. If factor V Leiden genotyping becomes less expensive, it could be cost effective to screen for the presence of the mutation before instituting HRT in women with coronary disease.

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    • "Administration of oral contraceptives increases the risk of venous thrombosis 16-fold in patients heterozygous for prothrombin mutation and 20- to 35-fold in patients heterozygous for factor V Leiden mutation.44–46 Factor V Leiden mutation increases also the risk of venous thrombosis in women receiving hormonal therapy.47–48 "
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    ABSTRACT: Factor V Leiden (R506Q) mutation is the most commonly observed inherited genetic abnormality related to vein thrombosis. Lebanon has one of the highest frequencies of this mutation in the world with a prevalence of 14.4% in the general population. The aim of this study is to define risk factors including inherited genetic abnormalities among Lebanese patients with lower extremity deep vein thrombosis. We report the clinical outcome of patients with thrombophilia. From January 1998 to January 2008, 162 patients (61 males and 101 females) were diagnosed with lower extremity deep vein thrombosis. Mean age was 61 years (range: 21 to 95 years). The most frequent risk factors for vein thrombosis were surgery, advanced age, obesity, and cancer. Twenty-five patients had thrombophilia, 16 patients had factor V Leiden (R506Q) mutation, and seven patients had MTHFR C677T mutation. Ninety-two percent of patients screened for thrombophilia were positive. Screening was requested in young patients (16), patients with recurrent (11), spontaneous (8), and extensive (5) venous thrombosis, familial history (5), pregnancy (4), estroprogestative treatment (3), and air travel (1). Nine patients had one, 11 patients had two, and five had three of these conditions. Follow-up (6 to 120 months) of these 25 patients treated with antivitamin K did not reveal recurrences or complications related to venous thromboembolism. Factor V Leiden mutation followed by MTHFR mutation are the most commonly observed genetic abnormalities in these series. Defining risk factors and screening for thrombophilia when indicated reduce recurrence rate and complications. Recommendations for thrombophilia screening will be proposed.
    Vascular Health and Risk Management 02/2009; 5:627-33.
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    • "Perhaps the most consistent risk for estrogenic treatment and venous thrombosis is Factor V Leiden. However, individuals who do not carry the mutation may be at risk for a thrombotic event while those who carry it may never experience an event (Heit, 2006; Herrington et al., 2002b; Miller et al., 2006; Price and Ridker, 1997; Simon et al., 2006). The formulation of the estrogenic treatment may also be critical for increasing risk even in individuals with this mutation, as incidence of venous thrombosis was less in individuals with Factor V Leiden using transdermal compared to oral estrogenic products (Scarabin et al., 2003; Straczek et al., 2005). "
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    ABSTRACT: The impact of estrogen exposure in preventing or treating cardiovascular disease is controversial. But it is clear that estrogen has important effects on vascular physiology and pathophysiology, with potential therapeutic implications. Therefore, the goal of this review is to summarize, using an integrated approach, current knowledge of the vascular effects of estrogen, both in humans and in experimental animals. Aspects of estrogen synthesis and receptors, as well as general mechanisms of estrogenic action are reviewed with an emphasis on issues particularly relevant to the vascular system. Recent understanding of the impact of estrogen on mitochondrial function suggests that the longer lifespan of women compared with men may depend in part on the ability of estrogen to decrease production of reactive oxygen species in mitochondria. Mechanisms by which estrogen increases endothelial vasodilator function, promotes angiogenesis, and modulates autonomic function are summarized. Key aspects of the relevant pathophysiology of inflammation, atherosclerosis, stroke, migraine, and thrombosis are reviewed concerning current knowledge of estrogenic effects. A number of emerging concepts are addressed throughout. These include the importance of estrogenic formulation and route of administration and the impact of genetic polymorphisms, either in estrogen receptors or in enzymes responsible for estrogen metabolism, on responsiveness to hormone treatment. The importance of local metabolism of estrogenic precursors and the impact of timing for initiation of treatment and its duration are also considered. Although consensus opinions are emphasized, controversial views are presented to stimulate future research.
    Pharmacological reviews 07/2008; 60(2):210-41. DOI:10.1124/pr.107.08002 · 17.10 Impact Factor
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    • "The relevance of the APC resistance phenotype has been shown by its association with risk of VTE in case–control studies (De Visser et al, 1999: Lowe et al, 2000a) and in prospective studies (Lindahl et al, 1999; Lowe et al, 1999b; Rodeghiero & Tosetto, 1999; Folsom et al, 2002a), most of which adjusted for the factor V Leiden mutation. The supraadditive effect on VTE risk when factor V Leiden is combined with pregnancy (Robertson et al, 2005), combined oral contraceptives (Vandenbroucke et al, 1994; Wu et al, 2005a) or oral HRT (Herrington et al, 2002; Rosendaal et al, 2002; Cushman et al, 2004a), could also be ascribed to supraadditive effects on APC resistance. However, standardisation of this phenotype is awaited and, at present, many haematology laboratories performing thrombophilia screens concentrate on determination of factor V Leiden, either by genetic assays, or by testing for APC resistance in factor V-deficient plasma. "
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    ABSTRACT: The risk of venous or arterial thrombosis is routinely assessed by clinical variables (risk factors) supplemented by measurement of blood lipids and glucose for arterial thrombotic events. Haematological tests that might play a role in risk prediction include haemostatic variables, haematocrit and inflammatory markers (erythrocyte sedimentation rate, plasma viscosity, white cell count). Recent epidemiological studies of these phenotypes and related genotypes are reviewed. For the risk prediction of first venous thrombosis, screening for thrombophilias in 'high-risk' situations does not appear clinically effective or cost-effective; with the possible exception of women considering oral hormone replacement therapy. General screening after a first venous event to predict recurrence (or risk in asymptomatic relatives) does not appear effective; with the possible exception of d-dimer, which requires further study. For risk prediction of first arterial thrombosis, screening adds little to prediction by current clinical risk scores. Screening of persons after a first arterial event, or with atrial fibrillation (e.g. with D-dimer for stroke prediction), requires further study. In conclusion, haematological tests have very limited roles in the prediction of cardiovascular risk, and should only be used according to evidence-based guidelines. The need for management studies is highlighted.
    British Journal of Haematology 06/2006; 133(3):232-50. DOI:10.1111/j.1365-2141.2006.06021.x · 4.71 Impact Factor
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